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Expert Opinion on Drug Discovery Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/iedc20
Challenges in drug discovery for overcoming ‘dysfunctional pain’: an emerging category of chronic pain Yukinori Nagakura
a
a
Aomori University, Faculty of Pharmaceutical Sciences, 2-3-1 Kohbata, Aomori-shi, Aomori 030-0943, Japan +81 17 738 2001; +81 17 738 2411; Published online: 11 Jul 2015.
Click for updates To cite this article: Yukinori Nagakura (2015): Challenges in drug discovery for overcoming ‘dysfunctional pain’: an emerging category of chronic pain, Expert Opinion on Drug Discovery To link to this article: http://dx.doi.org/10.1517/17460441.2015.1066776
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Editorial
1.
Introduction
2.
Conclusion
3.
Expert opinion
Challenges in drug discovery for overcoming ‘dysfunctional pain’: an emerging category of chronic pain Yukinori Nagakura
Downloaded by [Emory University] at 01:00 03 August 2015
Aomori University, Faculty of Pharmaceutical Sciences, Aomori, Japan
‘Dysfunctional pain’, a type of chronic pain, is associated with a broad range of clinical disorders, including fibromyalgia, irritable bowel syndrome and interstitial cystitis. It is emerging as a serious issue due to the negative impact of inexplicable pain on quality of life, lack of effective therapies and health care cost. Although drug discovery efforts in pain research have so far focused primarily on inflammatory and neuropathic pain, this editorial attracts attention to dysfunctional pain research and discusses a possible fundamental framework for tackling this difficult issue. While dysfunctional pain is characterized by chronic widespread or regional pain symptoms and occurrence of pain amplification, underlying pathophysiologies remain to be identified. Thus, a pivotal step in future research would be the exploration of pathophysiological pathways, such as relevant molecular networks, which are responsible for dysfunctional pain. Utilization of developing technologies paves the way for the identification of underlying pathophysiologies and the development of effective drugs which would eventually solve the clinical issues associated with dysfunctional pain. Keywords: drug discovery, dysfunctional pain, fibromyalgia, interstitial cystitis, irritable bowel syndrome, unknown pathophysiology Expert Opin. Drug Discov. [Early Online]
1.
Introduction
Dysfunctional pain is emerging as a large problem ‘Dysfunctional pain’, a type of chronic pain, described in a concise article regarding pain classifications by Woolf [1]. At present, it seems that dysfunctional pain is increasing its presence as a serious issue to be addressed. While other major categories of chronic pain, including inflammatory pain and neuropathic pain, result from identified causes, that is activation of immune system and damage to the nervous system, respectively, the cause of dysfunctional pain remains unknown. Dysfunctional pain is associated with a broad range of clinical symptom-based disorders, including fibromyalgia, irritable bowel syndrome (IBS), temporomandibular joint disease and interstitial cystitis. Patients with these disorders commonly suffer from inexplicable pain as a core symptom. Whether the pain is widespread (e.g., fibromyalgia) or regional (e.g., IBS), it causes persistent bouts of discomfort and has a significant negative influence on the quality of life [2,3]. Currently available therapeutics do not provide adequate relief of dysfunctional pain, whereas a minority of patients obtain substantial benefit [3,4]. Thus, it seems that patients with dysfunctional pain are forced to recurrently visit doctors to seek relief and are vulnerable to losses in productivity, absenteeism, disability and unemployment [5,6]. Given that the prevalence of dysfunctional pain is estimated to be quite high (2 -- 8% of the general population for fibromyalgia [7], 7 -- 21% of the general 1.1
10.1517/17460441.2015.1066776 © 2015 Informa UK, Ltd. ISSN 1746-0441, e-ISSN 1746-045X All rights reserved: reproduction in whole or in part not permitted
1
Y. Nagakura
population for IBS [8] and 0.05 -- 0.5% of the female population for interstitial cystitis/painful bladder syndrome [9]), dysfunctional pain has been emerging as a serious issue from both therapeutic and economic perspectives. Accordingly, effective drugs are required.
Underlying pathophysiologies remain to be identified
Downloaded by [Emory University] at 01:00 03 August 2015
1.2
Clinical disorders associated with dysfunctional pain are characterized by chronic widespread or regional pain symptoms and occurrence of pain amplification [10]. Patients with one disorder associated with dysfunctional pain (e.g., fibromyalgia) concomitantly experience other disorders (e.g., IBS) with high probability [11]. The significant overlap among these disorders might suggest that they share a common underlying pathophysiology. Studies using neuroimaging technology have suggested pain amplification in the CNS commonly occurs in patients with dysfunctional pain [12,13]. Given that patients exhibit a variety of pain phenotypes and comorbidities [14], it remains possible that they could be classified into subgroups based on underlying pathophysiologies. In either case, identification of the underlying pathophysiologies can be a vital factor in the advancement of dysfunctional pain medications. Exploration of trace (biomarker) associated with the pathophysiology is ongoing using various methodologies. For example, deficiencies in the growth hormone insulin-like growth factor cascade are associated with chronic pain at least in subgroup of patients with fibromyalgia [15]. A recent study using rectal biopsy samples has suggested that densities of rectal peptide YY and somatostatin cells are significantly altered in IBS patients [16]. Functional connectivity analysis by magnetic resonance imaging has identified altered connectivity in patients with dysfunctional pain [17,18]. Studies with greater scale would verify the linkage between the putative traces and the clinical symptoms of dysfunctional pain. At present, underlying pathophysiologies (e.g., triggering biological mechanisms and possible drug target molecules) of dysfunctional pain remain to be identified. Thus, further studies on the exploration of pathophysiologies should be warranted.
2.
Conclusion
Dysfunctional pain is associated with a broad range of clinical disorders and is emerging as a serious issue due to the negative impact of inexplicable pain on quality-of-life, lack of effective therapies, and health care cost. Dysfunctional pain is characterized by chronic widespread or regional pain symptoms and occurrence of pain amplification. Underlying pathophysiologies (e.g., triggering biological mechanisms and possible drug target molecules) remain to be identified. 2
3.
Expert opinion
Although drug discovery research in the pain field has so far focused primarily on inflammatory and neuropathic pain, intensive study on dysfunctional pain would be expected based on the background above. The first and pivotal step is exploration of pathophysiological pathways, such as relevant molecular networks, which are responsible for dysfunctional pain. To that end, it would be efficient and effective to apply a systems biology approach, which aims to understand and simulate biological systems using interactions of key biological elements. Once the underlying pathophysiology is identified as a relevant molecular network, it could be targeted for intervention. In the case where one molecule is assumed to play a dominant role in the identified network, selective modulator of the candidate molecule would be designed. In the alternative case where multiple different molecules are assumed to play important roles in the network, modulation of plural target molecules would be preferred for achieving an optimal effect. A drug with multifaceted actions (i.e., drug which has a potential ability to modulate the target molecules) would be pursued, or combinations of two or more drugs could be an optional approach. Furthermore, natural products would also be a possible source of substances with desirable effects [19], and nanotechnology would help carry hard-to-deliver substances such as proteins to the site of action in the body [20]. Because dysfunctional pain is an integrated entity, studies in whole systems, such as in vivo animal models, are indispensable to research dysfunctional pain. In particular, animal models that reflect the target pathophysiology responsible for dysfunctional pain are required. Currently, hypothesis-based animal models of dysfunctional pain include stress-induced visceral pain models (e.g., maternal separation, neonatal irritation, and high-anxiety WKY strain models) [21] and several putative fibromyalgia models (e.g., acid saline injections, biogenic amine depletion, cold stress and fatigue-enhanced muscle pain models) [22]. Given that dysfunctional pain in patients is associated with pain amplification in the central nervous system [10,12,13], manifestation of this phenomenon is essential in animal models. So far, the existence of mechanical and/or thermal hyperalgesia has suggested the occurrence of pain amplification in the animal models of dysfunctional pain [21,22]. The application of brain imaging technology to animal models of dysfunctional pain would provide information about the abnormal pain processing occurring in the brain and how it is associated with the hyperalgesia. Importantly, the malfunction of target networks should be verified as the cause of dysfunctional pain in animal models. For example, quantitative changes in molecules associated with the relevant network should be analyzed for verification. The combination use of quantitative biomarkers reflecting the malfunction of target networks and chronic pain-associated behavioral measures such as hyperalgesia could effectively evaluate drug candidates for dysfunctional pain.
Expert Opin. Drug Discov. (2015) 10(10)
Challenges in drug discovery for overcoming ‘dysfunctional pain’
The drug discovery research for dysfunctional pain is at an early stage. To the end of overcoming the emerging target dysfunctional pain, it would be essential to incorporate developing technologies such as systems biology, bioimaging, nanotechnology and biotechnology into the pain research. Utilization of such technologies paves the way for the identification of underlying pathophysiologies and the development of effective drugs which would eventually solve the clinical issues associated with dysfunctional pain. Bibliography
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Papers of special note have been highlighted as either of interest () or of considerable interest () to readers.
10.
Clauw DJ. Fibromyalgia and related conditions. Mayo Clin Proc 2015;90(5):680--92
1.
11.
Kim SE, Chang L. Overlap between functional GI disorders and other functional syndromes: what are the underlying mechanisms? Neurogastroenterol Motil 2012;24(10):895--913
..
Downloaded by [Emory University] at 01:00 03 August 2015
Declaration of interest
2.
Woolf CJ. What is this thing called pain? J Clin Invest 2010;120(11):3742--4 Important description of dysfunctional pain. Sarzi-Puttini P, Atzeni F, Di Franco M, et al. Dysfunctional syndromes and fibromyalgia: a 2012 critical digest. Clin Exp Rheumatol 2012;30(6 Suppl 74):143--51
3.
Halland M, Talley NJ. New treatments for IBS. Nat Rev Gastroenterol Hepatol 2013;10(1):13--23
4.
Ha¨user W, Walitt B, Fitzcharles MA, Sommer C. Review of pharmacological therapies in fibromyalgia syndrome. Arthritis Res Ther 2014;16(1):201
5.
6.
Hillila MT, Farkkila NJ, Farkkila MA. Societal costs for irritable bowel syndrome -- a population based study. Scand J Gastroenterol 2010;45(5):582--91 Skaer TL. Fibromyalgia: disease synopsis, medication cost effectiveness and economic burden. Pharmacoeconomics 2014;32(5):457--66
7.
Clauw DJ. Fibromyalgia: a clinical review. JAMA 2014;311(15):1547--55
8.
Chey WD, Kurlander J, Eswaran S. Irritable bowel syndrome: a clinical review. JAMA 2015;313(9):949--58
9.
Davis NF, Brady CM, Creagh T. Interstitial cystitis/painful bladder syndrome: epidemiology, pathophysiology and evidence-based treatment options. Eur J Obstet Gynecol Reprod Biol 2014;175:30--7
12.
.
Gracely RH, Petzke F, Wolf JM, Clauw DJ. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum 2002;46(5):1333--43 Important article highlight evidence of pain amplification in dysfunctional pain.
13.
Hampson JP, Reed BD, Clauw DJ, et al. Augmented central pain processing in vulvodynia. J Pain 2013;14(6):579--89
14.
McCarberg BH. Clinical overview of fibromyalgia. Am J Ther 2012;19(5):357--68
15.
Cuatrecasas G, Alegre C, Fernandez-Sola J, et al. Growth hormone treatment for sustained pain reduction and improvement in quality of life in severe fibromyalgia. Pain 2012;153(7):1382--9
16.
17.
El-Salhy M, Hatlebakk JG, Gilja OH, Hausken T. Densities of rectal peptide YY and somatostatin cells as biomarkers for the diagnosis of irritable bowel syndrome. Peptides 2015;67:12--19 Napadow V, Kim J, Clauw DJ, Harris RE. Decreased intrinsic brain connectivity is associated with reduced clinical pain in fibromyalgia. Arthritis Rheum 2012;64(7):2398--403
Expert Opin. Drug Discov. (2015) 10(10)
18.
Mayer EA, Gupta A, Kilpatrick LA, Hong JY. Imaging brain mechanisms in chronic visceral pain. Pain 2015;156(Suppl 1):S50--63
19.
Nascimento SS, Camargo EA, DeSantana JM, et al. Linalool and linalool complexed in b-cyclodextrin produce anti-hyperalgesic activity and increase Fos protein expression in animal model for fibromyalgia. Naunyn Schmiedebergs Arch Pharmacol 2014;387(10):935--42
20.
Botelho MA, Queiroz DB, Barros G, et al. Nanostructured transdermal hormone replacement therapy for relieving menopausal symptoms: a confocal Raman spectroscopy study. Clinics (Sao Paulo) 2014;69(2):75--82
21.
Moloney RD, O’Mahony SM, Dinan TG, Cryan JF. Stress-induced visceral pain: toward animal models of irritable-bowel syndrome and associated comorbidities. Front Psychiatry 2015;6:15 Useful article listing animal models of irritable bowel syndrome.
.
22.
.
DeSantana JM, da Cruz KM, Sluka KA. Animal models of fibromyalgia. Arthritis Res Ther 2013;15(6):222 Useful article listing animal models of fibromyalgia.
Affiliation Yukinori Nagakura Aomori University, Faculty of Pharmaceutical Sciences, 2-3-1 Kohbata, Aomori-shi, Aomori 030-0943, Japan Tel: +81 17 738 2001; Fax: +81 17 738 2411; E-mail: [email protected]
3
Expert Opinion on Drug Discovery Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/iedc20
Challenges in drug discovery for overcoming ‘dysfunctional pain’: an emerging category of chronic pain Yukinori Nagakura
a
a
Aomori University, Faculty of Pharmaceutical Sciences, 2-3-1 Kohbata, Aomori-shi, Aomori 030-0943, Japan +81 17 738 2001; +81 17 738 2411; Published online: 11 Jul 2015.
Click for updates To cite this article: Yukinori Nagakura (2015): Challenges in drug discovery for overcoming ‘dysfunctional pain’: an emerging category of chronic pain, Expert Opinion on Drug Discovery To link to this article: http://dx.doi.org/10.1517/17460441.2015.1066776
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Editorial
1.
Introduction
2.
Conclusion
3.
Expert opinion
Challenges in drug discovery for overcoming ‘dysfunctional pain’: an emerging category of chronic pain Yukinori Nagakura
Downloaded by [Emory University] at 01:00 03 August 2015
Aomori University, Faculty of Pharmaceutical Sciences, Aomori, Japan
‘Dysfunctional pain’, a type of chronic pain, is associated with a broad range of clinical disorders, including fibromyalgia, irritable bowel syndrome and interstitial cystitis. It is emerging as a serious issue due to the negative impact of inexplicable pain on quality of life, lack of effective therapies and health care cost. Although drug discovery efforts in pain research have so far focused primarily on inflammatory and neuropathic pain, this editorial attracts attention to dysfunctional pain research and discusses a possible fundamental framework for tackling this difficult issue. While dysfunctional pain is characterized by chronic widespread or regional pain symptoms and occurrence of pain amplification, underlying pathophysiologies remain to be identified. Thus, a pivotal step in future research would be the exploration of pathophysiological pathways, such as relevant molecular networks, which are responsible for dysfunctional pain. Utilization of developing technologies paves the way for the identification of underlying pathophysiologies and the development of effective drugs which would eventually solve the clinical issues associated with dysfunctional pain. Keywords: drug discovery, dysfunctional pain, fibromyalgia, interstitial cystitis, irritable bowel syndrome, unknown pathophysiology Expert Opin. Drug Discov. [Early Online]
1.
Introduction
Dysfunctional pain is emerging as a large problem ‘Dysfunctional pain’, a type of chronic pain, described in a concise article regarding pain classifications by Woolf [1]. At present, it seems that dysfunctional pain is increasing its presence as a serious issue to be addressed. While other major categories of chronic pain, including inflammatory pain and neuropathic pain, result from identified causes, that is activation of immune system and damage to the nervous system, respectively, the cause of dysfunctional pain remains unknown. Dysfunctional pain is associated with a broad range of clinical symptom-based disorders, including fibromyalgia, irritable bowel syndrome (IBS), temporomandibular joint disease and interstitial cystitis. Patients with these disorders commonly suffer from inexplicable pain as a core symptom. Whether the pain is widespread (e.g., fibromyalgia) or regional (e.g., IBS), it causes persistent bouts of discomfort and has a significant negative influence on the quality of life [2,3]. Currently available therapeutics do not provide adequate relief of dysfunctional pain, whereas a minority of patients obtain substantial benefit [3,4]. Thus, it seems that patients with dysfunctional pain are forced to recurrently visit doctors to seek relief and are vulnerable to losses in productivity, absenteeism, disability and unemployment [5,6]. Given that the prevalence of dysfunctional pain is estimated to be quite high (2 -- 8% of the general population for fibromyalgia [7], 7 -- 21% of the general 1.1
10.1517/17460441.2015.1066776 © 2015 Informa UK, Ltd. ISSN 1746-0441, e-ISSN 1746-045X All rights reserved: reproduction in whole or in part not permitted
1
Y. Nagakura
population for IBS [8] and 0.05 -- 0.5% of the female population for interstitial cystitis/painful bladder syndrome [9]), dysfunctional pain has been emerging as a serious issue from both therapeutic and economic perspectives. Accordingly, effective drugs are required.
Underlying pathophysiologies remain to be identified
Downloaded by [Emory University] at 01:00 03 August 2015
1.2
Clinical disorders associated with dysfunctional pain are characterized by chronic widespread or regional pain symptoms and occurrence of pain amplification [10]. Patients with one disorder associated with dysfunctional pain (e.g., fibromyalgia) concomitantly experience other disorders (e.g., IBS) with high probability [11]. The significant overlap among these disorders might suggest that they share a common underlying pathophysiology. Studies using neuroimaging technology have suggested pain amplification in the CNS commonly occurs in patients with dysfunctional pain [12,13]. Given that patients exhibit a variety of pain phenotypes and comorbidities [14], it remains possible that they could be classified into subgroups based on underlying pathophysiologies. In either case, identification of the underlying pathophysiologies can be a vital factor in the advancement of dysfunctional pain medications. Exploration of trace (biomarker) associated with the pathophysiology is ongoing using various methodologies. For example, deficiencies in the growth hormone insulin-like growth factor cascade are associated with chronic pain at least in subgroup of patients with fibromyalgia [15]. A recent study using rectal biopsy samples has suggested that densities of rectal peptide YY and somatostatin cells are significantly altered in IBS patients [16]. Functional connectivity analysis by magnetic resonance imaging has identified altered connectivity in patients with dysfunctional pain [17,18]. Studies with greater scale would verify the linkage between the putative traces and the clinical symptoms of dysfunctional pain. At present, underlying pathophysiologies (e.g., triggering biological mechanisms and possible drug target molecules) of dysfunctional pain remain to be identified. Thus, further studies on the exploration of pathophysiologies should be warranted.
2.
Conclusion
Dysfunctional pain is associated with a broad range of clinical disorders and is emerging as a serious issue due to the negative impact of inexplicable pain on quality-of-life, lack of effective therapies, and health care cost. Dysfunctional pain is characterized by chronic widespread or regional pain symptoms and occurrence of pain amplification. Underlying pathophysiologies (e.g., triggering biological mechanisms and possible drug target molecules) remain to be identified. 2
3.
Expert opinion
Although drug discovery research in the pain field has so far focused primarily on inflammatory and neuropathic pain, intensive study on dysfunctional pain would be expected based on the background above. The first and pivotal step is exploration of pathophysiological pathways, such as relevant molecular networks, which are responsible for dysfunctional pain. To that end, it would be efficient and effective to apply a systems biology approach, which aims to understand and simulate biological systems using interactions of key biological elements. Once the underlying pathophysiology is identified as a relevant molecular network, it could be targeted for intervention. In the case where one molecule is assumed to play a dominant role in the identified network, selective modulator of the candidate molecule would be designed. In the alternative case where multiple different molecules are assumed to play important roles in the network, modulation of plural target molecules would be preferred for achieving an optimal effect. A drug with multifaceted actions (i.e., drug which has a potential ability to modulate the target molecules) would be pursued, or combinations of two or more drugs could be an optional approach. Furthermore, natural products would also be a possible source of substances with desirable effects [19], and nanotechnology would help carry hard-to-deliver substances such as proteins to the site of action in the body [20]. Because dysfunctional pain is an integrated entity, studies in whole systems, such as in vivo animal models, are indispensable to research dysfunctional pain. In particular, animal models that reflect the target pathophysiology responsible for dysfunctional pain are required. Currently, hypothesis-based animal models of dysfunctional pain include stress-induced visceral pain models (e.g., maternal separation, neonatal irritation, and high-anxiety WKY strain models) [21] and several putative fibromyalgia models (e.g., acid saline injections, biogenic amine depletion, cold stress and fatigue-enhanced muscle pain models) [22]. Given that dysfunctional pain in patients is associated with pain amplification in the central nervous system [10,12,13], manifestation of this phenomenon is essential in animal models. So far, the existence of mechanical and/or thermal hyperalgesia has suggested the occurrence of pain amplification in the animal models of dysfunctional pain [21,22]. The application of brain imaging technology to animal models of dysfunctional pain would provide information about the abnormal pain processing occurring in the brain and how it is associated with the hyperalgesia. Importantly, the malfunction of target networks should be verified as the cause of dysfunctional pain in animal models. For example, quantitative changes in molecules associated with the relevant network should be analyzed for verification. The combination use of quantitative biomarkers reflecting the malfunction of target networks and chronic pain-associated behavioral measures such as hyperalgesia could effectively evaluate drug candidates for dysfunctional pain.
Expert Opin. Drug Discov. (2015) 10(10)
Challenges in drug discovery for overcoming ‘dysfunctional pain’
The drug discovery research for dysfunctional pain is at an early stage. To the end of overcoming the emerging target dysfunctional pain, it would be essential to incorporate developing technologies such as systems biology, bioimaging, nanotechnology and biotechnology into the pain research. Utilization of such technologies paves the way for the identification of underlying pathophysiologies and the development of effective drugs which would eventually solve the clinical issues associated with dysfunctional pain. Bibliography
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Papers of special note have been highlighted as either of interest () or of considerable interest () to readers.
10.
Clauw DJ. Fibromyalgia and related conditions. Mayo Clin Proc 2015;90(5):680--92
1.
11.
Kim SE, Chang L. Overlap between functional GI disorders and other functional syndromes: what are the underlying mechanisms? Neurogastroenterol Motil 2012;24(10):895--913
..
Downloaded by [Emory University] at 01:00 03 August 2015
Declaration of interest
2.
Woolf CJ. What is this thing called pain? J Clin Invest 2010;120(11):3742--4 Important description of dysfunctional pain. Sarzi-Puttini P, Atzeni F, Di Franco M, et al. Dysfunctional syndromes and fibromyalgia: a 2012 critical digest. Clin Exp Rheumatol 2012;30(6 Suppl 74):143--51
3.
Halland M, Talley NJ. New treatments for IBS. Nat Rev Gastroenterol Hepatol 2013;10(1):13--23
4.
Ha¨user W, Walitt B, Fitzcharles MA, Sommer C. Review of pharmacological therapies in fibromyalgia syndrome. Arthritis Res Ther 2014;16(1):201
5.
6.
Hillila MT, Farkkila NJ, Farkkila MA. Societal costs for irritable bowel syndrome -- a population based study. Scand J Gastroenterol 2010;45(5):582--91 Skaer TL. Fibromyalgia: disease synopsis, medication cost effectiveness and economic burden. Pharmacoeconomics 2014;32(5):457--66
7.
Clauw DJ. Fibromyalgia: a clinical review. JAMA 2014;311(15):1547--55
8.
Chey WD, Kurlander J, Eswaran S. Irritable bowel syndrome: a clinical review. JAMA 2015;313(9):949--58
9.
Davis NF, Brady CM, Creagh T. Interstitial cystitis/painful bladder syndrome: epidemiology, pathophysiology and evidence-based treatment options. Eur J Obstet Gynecol Reprod Biol 2014;175:30--7
12.
.
Gracely RH, Petzke F, Wolf JM, Clauw DJ. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum 2002;46(5):1333--43 Important article highlight evidence of pain amplification in dysfunctional pain.
13.
Hampson JP, Reed BD, Clauw DJ, et al. Augmented central pain processing in vulvodynia. J Pain 2013;14(6):579--89
14.
McCarberg BH. Clinical overview of fibromyalgia. Am J Ther 2012;19(5):357--68
15.
Cuatrecasas G, Alegre C, Fernandez-Sola J, et al. Growth hormone treatment for sustained pain reduction and improvement in quality of life in severe fibromyalgia. Pain 2012;153(7):1382--9
16.
17.
El-Salhy M, Hatlebakk JG, Gilja OH, Hausken T. Densities of rectal peptide YY and somatostatin cells as biomarkers for the diagnosis of irritable bowel syndrome. Peptides 2015;67:12--19 Napadow V, Kim J, Clauw DJ, Harris RE. Decreased intrinsic brain connectivity is associated with reduced clinical pain in fibromyalgia. Arthritis Rheum 2012;64(7):2398--403
Expert Opin. Drug Discov. (2015) 10(10)
18.
Mayer EA, Gupta A, Kilpatrick LA, Hong JY. Imaging brain mechanisms in chronic visceral pain. Pain 2015;156(Suppl 1):S50--63
19.
Nascimento SS, Camargo EA, DeSantana JM, et al. Linalool and linalool complexed in b-cyclodextrin produce anti-hyperalgesic activity and increase Fos protein expression in animal model for fibromyalgia. Naunyn Schmiedebergs Arch Pharmacol 2014;387(10):935--42
20.
Botelho MA, Queiroz DB, Barros G, et al. Nanostructured transdermal hormone replacement therapy for relieving menopausal symptoms: a confocal Raman spectroscopy study. Clinics (Sao Paulo) 2014;69(2):75--82
21.
Moloney RD, O’Mahony SM, Dinan TG, Cryan JF. Stress-induced visceral pain: toward animal models of irritable-bowel syndrome and associated comorbidities. Front Psychiatry 2015;6:15 Useful article listing animal models of irritable bowel syndrome.
.
22.
.
DeSantana JM, da Cruz KM, Sluka KA. Animal models of fibromyalgia. Arthritis Res Ther 2013;15(6):222 Useful article listing animal models of fibromyalgia.
Affiliation Yukinori Nagakura Aomori University, Faculty of Pharmaceutical Sciences, 2-3-1 Kohbata, Aomori-shi, Aomori 030-0943, Japan Tel: +81 17 738 2001; Fax: +81 17 738 2411; E-mail: [email protected]
3
